MOST CLOSELY HLA MATCHED ALLOGENEIC VIRUS SPECIFIC CYTOTOXIC T-LYMPHOCYTES (CTL)

HLA 最接近匹配的同种异体病毒特异性细胞毒性 T 淋巴细胞 (CTL)

• 批准号: 8356704
• 负责人: HELEN E HESLOP
• 金额: $ 0.2万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356704
• 关键词: Adenoviruses; Allogenic; Back; Blood Cells; Blood donor; Cells; Clinical Research; Complication; Cytomegalovirus; Cytotoxic T-Lymphocytes; Disabled Persons; Donor person; Freezing; Funding; Genes; Genetic; Grant; Hematological Disease; Hematopoietic Neoplasms; Human Herpesvirus 4; Immune; Immune system; Infection; Infusion procedures; Laboratories; Monitor; National Center for Research Resources; Patients; Principal Investigator; Research; Research Infrastructure; Research Personnel; Resources; Risk; Source; Stem cell transplant; T-Lymphocyte; Testing; Transplant Recipients; Transplantation; United States National Institutes of Health; Virus; Virus Diseases; cell killing; cost; graft vs host disease; monocyte; prevent; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT When patients undergo a hemopoietic stem cell transplant (HSCT) from a donor who is the best possible match to treat blood cancers or other blood diseases they have a risk of infection until they can grow a new immune system from the donor. During this period they may develop serious viral infections with Epstein Barr virus (EBV), cytomegalovirus and adenovirus being three of the most common viruses that can cause problems. Investigators have previously shown that it is possible to grow up special T cells called virus-specific CTLs from the transplant donor that can prevent and treat these viral infections when they are given back to the patient. However it takes 2-3 months to grow these cells so it is not a practical option to grow virus-specific CTLs from the transplant donor for every patient that gets an infection with one of these viruses. In this study, investigators will see if an alternative approach is to make banks of virus-specific CTLs from normal donors that could be stored frozen and then made available to treat subjects post transplant if they developed one of these viral infections. Virus-specific CTL lines will be grown from normal donors and frozen. To make the CTL lines we first infect blood cells called monocytes with a specially produced adenovirus (a vector) that also carries part of the Cytomegalovirus (CMV) gene. This is a disabled virus that cannot reproduce itself once infection has occurred so it cannot spread. These infected monocytes then stimulate the T cells to respond to adenoviruses and CMV, and kill the cells infected with these viruses. We then give a second stimulation to the T cells, using cells which are also infected with EBV (which we will make from donor blood by infecting them with EBV in the laboratory) so that the cells now recognize three viruses CMV, EBV and Adenovirus. Once we have made sufficient numbers of T cells we will test them to make sure they kill cells infected with these viruses and freeze them. If a transplant patient gets an infection with one of these viruses, and the infection persists despite standard therapy, he or she would be eligible to receive a suitably matched CTL line. The primary objective is to determine if this strategy is feasible and safe. One risk is that because the T cells we make are not a complete genetic (HLA) match for the recipient, they might attack the subject and cause a condition called graft versus host disease (GVHD). We will closely monitor for this complication. Secondary objectives are to determine the effects of the T cell infusion on the virus infection and to see if the recipients can stay immune to these viruses. We will also see how long the T cells survive.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 抽象的 当患者接受与治疗血癌或其他血液疾病最匹配的捐献者的造血干细胞移植（HSCT）时，他们有感染的风险，直到他们能够从捐献者那里长出新的免疫系统。在此期间，他们可能会出现严重的病毒感染，其中EB病毒（EBV）、巨细胞病毒和腺病毒是三种最常见的可能引起问题的病毒。研究人员此前已表明，有可能从移植供体中培养出称为病毒特异性 CTL 的特殊 T 细胞，当将其回输给患者时，可以预防和治疗这些病毒感染。然而，培养这些细胞需要 2-3 个月的时间，因此从移植供体中为每位感染其中一种病毒的患者培养病毒特异性 CTL 并不是一个实际的选择。 在这项研究中，研究人员将看看是否有一种替代方法是从正常供体中建立病毒特异性 CTL 库，这些 CTL 可以冷冻保存，然后在移植后用于治疗受试者，如果他们出现了其中一种病毒感染。 病毒特异性 CTL 系将从正常供体中培养并冷冻。为了制备 CTL 系，我们首先用特制的腺病毒（载体）感染称为单核细胞的血细胞，该腺病毒也携带部分巨细胞病毒 (CMV) 基因。这是一种被禁用的病毒，一旦感染就无法自我复制，因此无法传播。 这些受感染的单核细胞随后刺激 T 细胞对腺病毒和 CMV 做出反应，并杀死被这些病毒感染的细胞。然后，我们使用同样感染 EBV 的细胞（我们将在实验室中通过用 EBV 感染供体血液来制备）对 T 细胞进行第二次刺激，以便细胞现在识别三种病毒：CMV、EBV 和腺病毒。一旦我们制造出足够数量的 T 细胞，我们将对它们进行测试，以确保它们杀死感染这些病毒的细胞并将其冷冻。 如果移植患者感染其中一种病毒，并且尽管接受标准治疗，感染仍然存在，那么他或她将有资格接受适当匹配的 CTL 系。 主要目标是确定该策略是否可行且安全。一个风险是，由于我们制造的 T 细胞与受体的基因 (HLA) 不完全匹配，因此它们可能会攻击受试者并导致一种称为移植物抗宿主病 (GVHD) 的疾病。我们将密切监测这种并发症。 次要目标是确定 T 细胞输注对病毒感染的影响，并观察接受者是否能够保持对这些病毒的免疫力。我们还将观察 T 细胞的存活时间。